In ovine pregnancy, as well as human pregnancy, cortisol is elevated. Studies in our laboratory suggest that the increase in cortisol is required for normal pregnancy outcome, and results from reset of regulated cortisol. Studies in women with Addison's disease also suggest that increased glucocorticoid action at term is crucial. We have found that reduction in maternal cortisol results in a deficiency in the normal expansion of maternal plasma volume. This model also causes reduced fetal blood pressure and increased incidence of fetal hypoxia and fetal and maternal death. In nonpregnant ewes cortisol increases blood pressure and heart rate, and decreases baroreflex sensitvity;adrenalectomy and total withdrawal from adrenal steroids causes decreased arterial pressure and dramatic phasic changes in blood pressure, suggesting disruption of the baroreflex. The proposed studies are designed to address the hypothesis that increases in cortisol contribute to the normal decrease in baroreflex sensitivity in pregnancy by effects within the CNS, as well as by indirect effects on blood volume. We further hypothesize that these effects are modulated by progesterone and estradiol, and that the vulnerability of the late gestation pregnant ewe to decreases in plasma cortisol is caused by changes in blood volume and/or progesterone. Four aims are proposed: 1) to test for effects of cortisol by inducing increases and decreases in cortisol, 2) to test for an effect of cortisol in the brainstem, using hindbrain implants containing cortisol receptor (MR or GR) antagonists, 3) to test for interactions of estradiol and progesterone with cortisol, using systemic implants of progesterone and/or estradiol or progesterone withdrawal, while allowing for or blocking the induced changes in plasma volume, 4) to test for changes in gene expression in brain areas involved in the baroreflex after manipulation of cortisol or placental steroid levels, including NTS, RVLM, and nucleus ambiguous. Endpoints to be examined are blood pressure and heart rate, baroreflex sensistivity, and analysis of the heart period and systolic pressure variability to determine relative sympathetic and parasympathetic tone. Although Addison's disease in pregnancy is rare, understanding of the role of the normal increase in cortisol, and potential effects of glucocorticoid withdrawal in pregnancy, is important to treatment of pregnant women at term and to the treatment of disturbances in blood volume or blood pressure in pregnancy. PUBLIC HEALTH RELEVANCE: The baroreflex, which regulates minute to minute changes in blood pressure, is less sensitive in pregnant women than in the nonpregnant individual, and this change helps to maintain the low resting blood pressure and relatively high sympathetic activity that are characteristic of pregnancy. In nonpregnant animal models, the adrenal hormone, cortisol, and the placental hormone, progesterone, appear to decrease baroreflex sensitivity, whereas disruption of maternal cortisol secretion in pregnancy caused with Addison's disease in humans, or with experimental manipulation in animals, results in hypotensive crisis and inability to regulate blood pressure if it occurs during the period of decreased plasma progesterone. In this project we will investigate the mechanism of adrenal steroids and progesterone effects in pregnancy, and test the hypothesis that interaction of cortisol and progesterone are required for the normal baroreflex changes in pregnancy.